Osmotic device containing pseudoephedrine and an H1 antagonist

ABSTRACT

The present invention provides an osmotic device containing controlled release pseudoephedrine in the core in combination with a rapid release H1 antagonist in an external coat. A wide range of H1 antagonist antihistamines, especially fexofenadine, can be used in this device. Particular embodiments of the invention provide osmotic devices having predetermined release profiles. One embodiment of the osmotic device includes an external coat that has been spray coated rather compression coated onto the device. The device with spray coated external core is smaller and easier to swallow than the similar device having a compression coated external coat. The device is useful for the treatment of respiratory congestion related disorders and allergy related disorders. The present devices provide PS and an H1 antagonist according to specific release profiles in combination with specific formulations.

This application claims the benefit of provisional application No.60/175,878, filed Jan. 13, 2000.

FIELD OF THE INVENTION

This invention pertains to an osmotic device containing pseudoephedrineand an H1 antagonist, or antihistamine. More particularly, it pertainsto an osmotic device tablet, which provides a controlled release ofpseudoephedrine and a rapid or immediate release of an H1 antagonist.

BACKGROUND OF THE INVENTION

Antihistamines, such as H1 antagonists, are used to treat seasonalallergic rhinitis (SAR); however, antihistamines do not effectivelytreat nasal congestion, e.g., stuffed or blocked nasal passages.Pseudoephedrine (Ps, a nasal decongestant) is widely used for thetreatment of nasal congestion and other related diseases or disorders;however, it does not effectively treat SAR. Therefore,antihistamine/nasal decongestant combinations are frequently used tomore effectively treat SAR.

The antihistamine and nasal decongestant can be administered in singleor multiple dosage forms. Single dosage unit combination dosage formscontaining a combination of Ps with an H1 antagonist, such asloratadine, cetirizine, fexofenadine, terfenadine, acrivastine orastemizole, are known. These combination tablet dosage forms generallyprovide a rapid release of the antihistamine and a controlled release ofPs. For example, Allegra-D™, Claritin-D™, Claritin-D™ 24-Hour,Seldane-D™ and Semprex-D™ (capsule) dosage forms are commerciallyavailable products that provide a rapid release of an H1 antagonist anda controlled or sustained release of Ps. These tablets are generallymade for once- or twice-daily administration. U.S. Pat. No. 6,051,585 toWeinstein et al. discloses a combination formulation containingpseudoephedrine, with limited duration of action, and an antihistaminefor treating SAR.

Applicant's note that Hoechst Marion Roussel has attemptedunsuccessfully to develop sustained release osmotic device product thatprovides therapeutic blood plasma levels of PS and FEX over a 24 hourperiod.

Sussman et al. (J. Allergy Clin. Immunol. (1999 July), 104(1), pp.100-106) have reported on the evaluation of the twice daily combinedadministration of fexofenadine and pseudoephedrine using two separatedosage forms: an immediate release form containing 60 mg of FEX and asustained release form containing 120 mg of PS.

Fexofenadine (terfenadine carboxylate) and derivatives are known for thetreatment of SAR. U.S. Pat. No. 4,254,129 to Carr et al., No. 5,375,693to Woosley et al., No. 5,578,610 to D'Ambra, and No. 6,037,353 disclosethe use of fexofenadine and related compounds in treating SAR.

Osmotic devices and other tablet formulations are known for theirability to provide a controlled release of a wide range of drugs. Suchosmotic devices and other tablet formulations are disclosed in U.S. Pat.No. 4,014,334 to Theeuwes et al., U.S. Pat. No. 4,576,604 to Guittard etal., Argentina Patent No. 234,493, U.S. Pat. No. 4,673,405 to Guittardet al., U.S. Pat. No. 5,558,879 to Chen et al., U.S. Pat. No. 4,810,502to Ayer et al., U.S. Pat. No. 4,801,461 to Hamel et al., U.S. Pat. No.5,681,584 to Savastano et al., U.S. Pat. No. 3,845,770, U.S. Pat. No.4,008,719 to Theeuwes et al., U.S. Pat. No. 4,058,122 to Theeuwes etal., U.S. Pat. No. 4,116,241 to Theeuwes et al., U.S. Pat. No. 4,160,452to Theeuwes, U.S. Pat. No. 4,256,108 to Theeuwes, and Argentina PatentNo. 199,301, the entire disclosures of which are hereby incorporated byreference. In particular, tablet formulations for providingantihistamines are disclosed in U.S. Pat. No. 4,650,807 to Findlay etal., and U.S. Pat. No. 4,501,893 to Findlay et al., the entiredisclosures of which are hereby incorporated by reference.

While conventional sustained release dosage forms, such as describedabove, are effective, osmotic devices such as those described by Faouret al. (U.S. Pat. No. 6,004,582), the entire disclosure of which ishereby incorporated by reference, are particularly advantageous fordelivering two different dosage forms from a single osmotic devicetablet. While Faour et al. disclose osmotic device formulationscomprising slow release pseudoephedrine with rapid release loratadineand slow release pseudoephedrine with rapid release astemizol, they donot disclose osmotic devices that provide the specific formulations,plasma profiles or release profiles for the various differentcombinations claimed herein, nor osmotic devices having adrug-containing external coat that has been spray coated rather thancompression coated onto the device.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides an osmotic devicecomprising:

a core comprising a therapeutically effective amount of pseudoephedrine(PS) and at least one osmotic agent or osmopolymer, wherein the coreprovides a controlled release of pseudoephedrine;

a semipermeable membrane surrounding the core and having a passagewaythere through; and

an external coat comprising a therapeutically effective amount of an H1antagonist, wherein the external coat provides a rapid release of the H1antagonist; wherein:

at least 67% of the pseudoephedrine is released within 23 hours, and atleast 65% of the H1 antagonist is released within 40 minutes afterexposure of the osmotic device to an aqueous solution.

In some embodiments, the H1 antagonist is selected from the groupconsisting of acrivastine, astemizol, azelastine, cetirizine, ebastine,epinastine, fexofenadine, loratadine, mizolastine, norastemizol,prometazine and terfenadine.

In other embodiments, the external coat is applied by spray coatingrather than by compression coating. By spray coating rather thancompression coating the external coat is thinner, and therefore asmaller osmotic device is formed.

Other embodiments include those wherein: 1) at least 75% of the H1antagonist is released within 30 min after administration; 2) at least75% of the H1 antagonist is released in 20 min after administration; 3)at least 75% of the H1 antagonist is released within 10 min afteradministration; 4) at least 75% of the H1 antagonist is released within5 min after administration; 5) all of the H1 antagonist is releasedwithin 90 min after administration; 6) all of the H1 antagonist isreleased within 45 min after administration; 7) all of the H1 antagonistis released within 30 min after administration; 8) all of the H1antagonist is released within 20 min after administration; 9) all of theH1 antagonist is released within 10 min after administration; 10) all ofthe H1 antagonist is released within 5 min after administration; 11) theosmotic device further comprises an inert and erodible water solublelamina interposed the semipermeable membrane and the drug-containingouter coating; 12) the water soluble lamina comprisespoly(vinylpyrrolidone)-(vinyl acetate) copolymer; 13) all of the H1antagonist is released within 120 min after administration; and/or 14)all of the H1 antagonist is released within 180 min afteradministration.

Still other embodiments include those wherein: 1) 10-25% of the PS isreleased within 3 hours after administration; 2) 25-50% of the PS isreleased within 7 hours after administration; 3) 50-66% of the PS isreleased within 11 hours after administration; 4) 66-79% of the PS isreleased within 15 hours after administration; and 5) 79-100% of the PSis released within 23 hours after administration or 79-90% of the PS isreleased within 23 hours after administration. Generally, all of the PSis released within 24 hours min after administration.

Another embodiment includes one wherein: 1) 5-23% of the PS is releasedwithin 3 hours after administration; 2) 20-52% of the PS is releasedwithin 7 hours after administration; 3) 36-72% of the PS is releasedwithin 11 hours after administration; 4) 53-82% of the PS is releasedwithin 15 hours after administration; and 5) 67-100% of the PS isreleased within 23 hours after administration.

More embodiments include those wherein: 1) 8-12% of the PS is releasedwithin 3 hours after administration; 2) 25-32% of the PS is releasedwithin 7 hours after administration; 3) 42-52% of the PS is releasedwithin 11 hours after administration; 4) 55-70% of the PS is releasedwithin 15 hours after administration; and 5) at least 75% of the PS isreleased within 23 hours after administration or 75-100% of the PS isreleased within 23 hours after administration.

Even other embodiments of the invention include those wherein: 1) 9-11%of the PS is released within 3 hours; 2) 19-22% of the PS is releasedwithin 5 hours; 3) 28-31% of the PS is released within 7 hours; 4)35-40% of the PS is released within 9 hours; 5) 45-50% of the PS isreleased within 11 hours; 6) 50-55% of the PS is released within 13hours; 7) 60-65% of the PS is released within 15 hours; and 8) at least67% of the PS is released within 23 hours after exposure to an aqueousenvironment.

Yet another embodiment of the invention includes one wherein: 1) 5-23%of the PS is released within 3 hours; 2) 12-38% of the PS is releasedwithin 5 hours; 3) 20-52% of the PS is released within 7 hours; 4)28-62% of the PS is released within 9 hours; 5) 36-72% of the PS isreleased within 11 hours; 6) 44-77% of the PS is released within 13hours; 7) 53-82% of the PS is released within 15 hours; and 8) at least67% of the PS is released within 23 hours after exposure to an aqueousenvironment.

Still yet another embodiment of the invention includes an osmotic devicewherein: 1) 5-23% of the PS is released within 3 hours; 2) 20-52% of thePS is released within 7 hours; 3) 36-72% of the PS is released within 11hours; 4) 53-82% of the PS is released within 15 hours; and 5) at least67% of the PS is released within 23 hours after exposure to an aqueousenvironment.

Yet other embodiments includes those wherein the PS is released at azero order or pseudo-zero order rate for a period of at least 12 hours,at least 14 hours, at least 16 hours, at least 18 hours and at least 20hours.

Another aspect of the invention provides a method of treating arespiratory congestion related disorder, such as nasal congestion, or anallergy related disorder, such as allergic rhinitis, in a mammal. Themethod comprises the step of administering an osmotic device, whichprovides a controlled release of pseudoephedrine from its core and arapid release of an H1 antagonist from an external coat, wherein atleast 75% of the H1 antagonist is released within about 40 minutes andat least about 67% of the pseudoephedrine is released within about 23hours.

In other embodiments, the osmotic device has a pseudoephedrine releaseprofile similar to that shown in FIG. 1 or 2.

Target therapeutic levels for the H1 antagonist are in the range ofabout 2 ng to about 700 ng per ml of plasma.

Target therapeutic levels for the pseudoephedrine are generally in therange of about 3 ng to about 1000 ng per ml of plasma.

The osmotic device generally delivers the H1 antagonist to the upper GItract and the pseudoephedrine to the middle to lower GI tract.

Another aspect of the invention provides an osmotic device comprising:

(a) a core comprising a therapeutically effective amount ofpseudoephedrine which is delivered at a controlled rate over a period ofabout 18-24 hours;

(b) a semipermeable membrane surrounding the core and a passagewaythrough the semipermeable membrane;

(c) an inert water soluble coating surrounding the semipermeablemembrane and plugging the passageway; and

(d) a fexofenadine-containing water soluble coating surrounding theinert coating for delivering a therapeutically effective amount offexofenadine at a rapid rate over a period of less than about 90 min.

Some specific embodiments of the invention also include those whereinthe drug-containing water soluble coating is present in an amount ofabout 1-90% wt., 9-40% wt., at least about 25% wt., about 25-40% wt. orabout 30-40% wt. based upon the total weight of the osmotic device.

Other features, advantages and embodiments of the invention will becomeapparent to those skilled in the art by the following description,accompanying examples.

BRIEF DESCRIPTION OF THE FIGS.

The following drawings are part of the present specification and areincluded to further demonstrate certain aspects of the invention. Theinvention may be better understood by reference to one or more of thesedrawings in combination with the detailed description of the specificembodiments presented herein.

FIG. 1 depicts an in vitro dissolution profile of pseudoephedrinereleased from the exemplary formulation of Example 1.

FIG. 2 depicts an in vitro dissolution profile of pseudoephedrinereleased from the exemplary formulation of Example 4. The data is anaverage of six different samples.

FIG. 3 depicts an in vitro release profile of fexofenadine (FEX)released from the exemplary formulation of Example 4.

DETAILED DESCRIPTION OF THE INVENTION

Pseudoephedrine and H1 antagonist antihistamines are available fromlarge number of commercial sources. The invention provides for theadministration of pseudoephedrine and H1 antagonists in their free base,free acid, racemic, optically pure, diastereomeric and/orpharmaceutically acceptable salt forms. Suitable H1 antagonistantihistamines include, for example, first generation antihistamines,second generation antihistamines, diphenhydramine, chlorpheniramine,brompheniramine, tripolidine, promethacine, hydroxizine, pinlamine,dimenhydrinate, acrivastine, azelastine, cetirizine, ebastine,epinastine, fexofenadine, loratadine, mizolastine, norastemizol andprometazine.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the therapeutic compound is modifiedby making acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of the Ps or H1 antagonist. The pharmaceutically acceptablesalts include the conventional non-toxic salts, for example, fromnon-toxic inorganic or organic acids. For example, such conventionalnon-toxic salts include those derived from inorganic acids such ashydrochloric, hydrobromic, sulfuric, sulfonic, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asamino acids, acetic, propionic, succinic, glycolic, stearic, lactic,malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic,phenylacetic, glutamic, benzoic, salicylic, sulfanilic,2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, and other known to those of ordinaryskill in the pharmaceutical sciences. Lists of suitable salts are foundin texts such as Remington's Pharmaceutical Sciences, 18th Ed. (AlfonsoR. Gennaro, ed.; Mack Publishing Company, Easton, Pa., 1990); Remington:the Science and Practice of Pharmacy 19^(th) Ed.(Lippincott, Williams &Wilkins, 1995); Handbook of Pharmaceutical Excipients, 3^(rd) Ed.(Arthur H. Kibbe, ed.; Amer. Pharmaceutical Assoc., 1999); thePharmaceutical Codex: Principles and Practice of Pharmaceutics 12^(th)Ed. (Walter Lund ed.; Pharmaceutical Press, London, 1994); The UnitedStates Pharmacopeia: The National Formulary (United States PharmacopeialConvention); and Goodman and Gilman's: the Pharmacological Basis ofTherapeutics (Louis S. Goodman and Lee E. Limbird, eds.; McGraw Hill,1992), the disclosures of which are hereby incorporated by reference.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

FIG. 1 depicts a pseudoephedrine in vitro dissolution profile for theosmotic device tablets described in Example 1. The release profile ofeach osmotic device generally resembles a pseudo-zero order orfirst-order release profile, as seen in FIG. 1. The release profile ofthe osmotic device of the invention will vary from that shown in FIG. 1according to the materials used to form the core and the semipermeablemembrane covering the core. For example, the release profile can beinfluenced by the material used to form the semipermeable membranecovering the core, by the material used to form any coating on thesemipermeable membrane, by the excipients present in the core, or by thepresence of an osmagent in the core. The osmotic device of the inventioncan have a release profile that generally resembles a pseudo-zero orderor a zero order release profile.

Depending upon the particular combination of ingredients used to preparethe osmotic device, the osmotic device will generally provide anexpected overall pseudoephedrine release profile resembling apseudo-zero order or first-zero release profile. The release profile forthe formulation of Example 1 is generally described as follows, whereinthe numbers in parentheses represent average values:

Time after Maximum Percent administration (h) Released Minimum PercentReleased 1 2-3 (2.5)  0.1-0.5 (0.4)  3 11-12 (11.9) 8-9 (8.6)  5 22-23(22.1) 18-20 (18.4) 7 30-32 (31.5) 25-27 (26.5) 9 40-42 (40.4) 33-35(34.4) 11 50-52 (51.6) 42-45 (44.2) 13 55-60 (57.5) 45-51 (49.9) 1565-70 (66.5) 55-60 (57.0) 23  75-100 (84.4) 60-75 (72.8)

The pseudoephedrine release profile can also be described as follows:

Time after administration (h) Released (%) (Avg.) 1 1-2 (1.6)  3  9-11(10.5) 5 19-22 (20.6) 7 28-31 (29.2) 9 35-40 (37.7) 11 45-50 (47.8) 1350-55 (53.7) 15 60-65 (61.7) 23 75-80 (78.0)

All of the tablet formulations of the invention will providetherapeutically effective levels of pseudoephedrine and an H1 antagonistfor at least a predetermined period of time. The tablets of theinvention will generally provide therapeutically effective amounts ofpseudoephedrine for a period of not less than 18 hours and not more than30 hours, not less than 20 hours and not more than 28 hours, not lessthan 18 hours and not more than 24 hours, or not less than 22 hours andnot more than 24 hours.

The formulation of Example 4 provides a fexofenadine (FEX) dissolutionprofile as depicted in FIG. 3 and a PS dissolution profile as depictedin FIG. 2. The PS release profile depicted in FIG. 2 includes data fromsix different analyses of the formulation of Example 4. The PS releaseprofile of FIG. 2 is generally described as follows:

Time after Maximum Percent administration (h) Released Minimum PercentReleased 3 18-25 (21.6)  8-12 (11.8) 7 40-50 (46.6) 30-36 (33.2) 1160-70 (66.4) 48-55 (51.5) 15 70-80 (78.3) 60-70 (66.5) 23  80-100 (85.3)70-80 (79.8)

The pseudoephedrine release profile can also be described as follows:

Time after administration (h) Released (%) (Avg.) 3 11-25 (16.3) 7 25-50(39.2) 11 50-66 (58.7) 15 66-79 (73.1) 23 79-86 (83.1)

The external coating can be an immediately dissolving coating thatdissolves in the buccal cavity or a rapidly dissolving coating thatdissolves in the stomach, jejunum or duodenum. The controlled releasecore generally begins to release pseudoephedrine within about 0.5-3hours or 0.5-2 hours after administration or within less than about 1hour after administration.

The rapid release coating will release all of the H1 antagonist withinthree hours after administration and at least 75% of its H1 antagonistwithin about 40 minutes after administration. Approximately all of theFEX is released from the formulation of Example 4 in less than 20 min,or in about 15 min, as depicted in FIG. 3.

In the various formulations exemplified herein, the weight ratio of thecore and the drug-containing coating with respect to the total weight ofthe device varies as follows.

Example Core Drug Coating Total tablet Weight (No.) (% wt.) (% wt.) (mg)1 74.5 9.9 563.1 4 54.1 35.8 775 5 61.9 25.8 677.5 6 74.8 10.7 560.5 755.6 34.1 755 8 61.5 26.4 682.5

Accordingly, the osmotic device of the present invention comprises adrug-containing water soluble coating present in an amount of about9-40% wt., at least about 25% wt., about 25-40% wt. and about 30-40% wt.based upon the total weight of the osmotic device. The higher weightranges are remarkable, since no prior art osmotic devices are known thatinclude a sprayed drug-containing water soluble coating present in suchhigh amounts. Also, the core is present in an amount of about 50-80%wt., about 50-75% wt., about 50-65% wt., or about 54-63% wt. based uponthe total weight of the device.

The osmotic device of Example 4 (240 mg PS extended release, and 180 mgFEX immediate release) was administered to 13 healthy humans todetermine the bioavailability of FEX in the osmotic device as comparedto that of the Allegra® (Hoechst Marion Roussel Inc.), which is animmediate release formulation of FEX (180 mg). The bioavailability wasdetermined by measuring blood plasma levels of FEX. The results indicatethat the FEX bioavailability for the claimed product was slightly higherwithin the first hour and lower within the following 29 hours afteradministration. Overall, the area under the curve was similar for bothsamples tested.

Those of ordinary skill in the art will appreciate that the particularamounts of pseudoephedrine and H1 antagonist used in the osmotic devicewill vary according to, among other things, the desired pharmacokineticbehavior in a mammal.

A water soluble coating, inert or drug-containing, will generallycomprise an inert and non-toxic material which is at least partially,and optionally substantially completely, soluble or erodible in anenvironment of use. Selection of materials suitable for the inert ordrug-containing water soluble coatings will depend upon the desiredrelease rate of drug from the drug-containing coating and upon thedesired separation of drug delivery from the core versus thedrug-containing coating. A rapidly dissolving coat will be soluble inthe buccal cavity and/or upper GI tract, such as the stomach, duodenum,jejunum or upper small intestines. Exemplary materials are disclosed inU.S. Pat. No. 4,576,604 to Guittard et al. and No. 4,673,405 to Guittardet al., and No. 6,004,582 to Faour et al. and the text PharmaceuticalDosage Forms: Tablets Volume I, 2^(nd) Edition. (A. Lieberman. ed. 1989,Marcel Dekker, Inc.), the relevant disclosures of which are herebyincorporated by reference. In some embodiments, the rapidly dissolvingcoat will be soluble in saliva, gastric juices, or acidic fluids.

Materials which are suitable for making the water soluble coatings ofthe invention include, by way of example and without limitation, watersoluble polysaccharide gums such as carrageenan, fucoidan, gum ghatti,tragacanth, arabinogalactan, pectin, and xanthan; water-soluble salts ofpolysaccharide gums such as sodium alginate, sodium tragacanthin, andsodium gum ghattate; water-soluble hydroxyalkylcellulose wherein thealkyl member is straight or branched of 1 to 7 carbons such ashydroxymethylcellulose, hydroxyethylcellulose, andhydroxypropylcellulose; synthetic water-soluble cellulose-based laminaformers such as methyl cellulose and its hydroxyalkyl methylcellulosecellulose derivatives such as a member selected from the groupconsisting of hydroxyethyl methylcellulose, hydroxypropylmethylcellulose, and hydroxybutyl methylcellulose; croscarmellosesodium; other cellulose polymers such as sodium carboxymethylcellulose;and other materials known to those of ordinary skill in the art. Otherlamina forming materials that can be used for this purpose includepoly(vinylpyrrolidone), polyvinylalcohol, polyethylene oxide, a blend ofgelatin and polyvinyl-pyrrolidone, gelatin, glucose, saccharides,povidone, copovidone, poly(vinylpyrrolidone)-poly(vinyl acetate)copolymer. The water soluble coating can comprise other pharmaceuticalexcipients that do or do not alter the way in which the water solublecoating behaves. The artisan of ordinary skill will recognize that theabove-noted materials include film forming polymers.

Other materials which can be used in the water soluble coatings includehydroxypropylcellulose, microcrystalline cellulose (MCC, Avicel.TM. fromFMC Corp.), poly(ethylene-vinyl acetate) (60:40) copolymer (EVAC fromAldrich Chemical Co.), 2-hydroxyethylmethacrylate (HEMA), MMA,terpolymers of HEMA:MMA:MA synthesized in the presence ofN,N′-bis(methacryloyloxyethyloxycarbonylamino)-azobenzene, azopolymers,enteric coated timed release system (Time Clock® from PharmaceuticalProfiles, Ltd., UK) and calcium pectinate can be included in the watersoluble coat.

The inert water soluble coat covering the semipermeable wall andblocking the passageway is made of synthetic or natural material which,through selective dissolution or erosion shall allow the passageway tobe unblocked thus allowing the process of osmotic delivery to start.This slow or fast dissolving water soluble coat can be impermeable to afirst external fluid, while being soluble in a second external fluid.This property can help to achieve a controlled and selective release ofthe active compound in the nucleus.

In some embodiments, the inert water soluble coat will be insoluble inthe fluid of a first environment of use, such as gastric juices, acidicfluids, or polar liquids, and soluble or erodible in the fluid of asecond environment of use, such as intestinal juices, substantially pHneutral or basic fluids, or apolar liquids. A wide variety of otherpolymeric materials are known to possess these various solubilityproperties and can be included in the water soluble coat. Such otherpolymeric materials include, by way of example and without limitation,cellulose acetate phthalate (CAP), cellulose acetate trimelletate (CAT),poly(vinyl acetate)phthalate (PVAP), hydroxypropyl methylcellulosephthalate (HP), poly(methacrylate ethylacrylate) (1:1) copolymer(MA-EA), poly(methacrylate methylmethacrylate) (1:1) copolymer (MA-MMA),poly(methacrylate methylmethacrylate) (1:2) copolymer, Eudragit™ L-30-D(MA-EA, 1:1), Eudragit™ L-100-55 (MA-EA, 1:1),hydroxypropylmethylcellulose acetate succinate (HPMCAS), Coateric™(PVAP), Aquateric™ (CAP), AQOAT™ (HPMCAS) and combinations thereof. Thewater soluble coat can also comprise dissolution aids, stabilitymodifiers, and bioabsorption enhancers.

An optional polymeric material for use in the inert water soluble coatincludes enteric materials that resist the action of gastric fluidavoiding permeation through the semipermeable wall while one or more ofthe materials in the core are solubilized in the intestinal tractthereby allowing delivery of a drug in the core by osmotic pumping tobegin. A material that easily adapts to this kind of requirement is apoly(vinylpyrrolidone)-vinyl acetate copolymer, such as the materialsupplied by BASF under its Kollidon VA64 trademark, mixed with magnesiumstearate and other similar excipients. The water soluble coat can alsocomprise povidone, which is supplied by BASF under its Kollidon K 30trademark, and hydroxypropyl methylcellulose, which is supplied by Dowunder its Methocel E-15 trademark. The materials can be prepared insolutions having different concentrations of polymer according to thedesired solution viscosity. For example, a 10% P/V aqueous solution ofKollidon™ K 30 has a viscosity of about 5.5-8.5 cps at 20.degree. C.,and a 2% P/V aqueous solution of Methocel™ E-15 has a viscosity of about13-18 cps at 20.degree. C.

The inert water soluble coat can also comprise other materials suitablewhich are substantially resistant to gastric juices and which willpromote either enteric or colonic release. For this purpose, the inertwater soluble coat can comprise one or more materials that do notdissolve, disintegrate, or change their structure in the stomach andduring the period of time that the osmotic device resides in thestomach. Representative materials that keep their integrity in thestomach can comprise a member selected from the group consisting of (a)keratin, keratin sandarac-tolu, salol (phenyl salicylate), salolbeta-naphthylbenzoate and acetotannin, salol with balsam of Peru, salolwith tolu, salol with gum mastic, salol and stearic acid, and salol andshellac; (b) a member selected from the group consisting of formalizedprotein, formalized gelatin, and formalized cross-linked gelatin andexchange resins; (c) a member selected from the group consisting ofmyristic acid-hydrogenated castor oil-cholesterol, stearic acid-muttontallow, stearic acid-balsam of tolu, and stearic acid-castor oil; (d) amember selected from the group consisting of shellac, ammoniatedshellac, ammoniated shellac-salol, shellac-wool fat, shellac-acetylalcohol, shellac-stearic acid-balsam of tolu, and shellac n-butylstearate; (e) a member selected from the group consisting of abieticacid, methyl abictate, benzoin, balsam of tolu, sandarac, mastic withtolu, and mastic with tolu, and mastic with acetyl alcohol; (f) acrylicresins represented by anionic polymers synthesized from methacrylateacid and methacrylic acid methyl ester, copolymeric acrylic resins ofmethacrylic and methacrylic acid and methacrylic acid alkyl esters,copolymers of alkacrylic acid and alkacrylic acid alkyl esters, acrylicresins such asdimethylaminoethylmethacrylate-butylmethacrylate-methylmethacrylatecopolymer of 150,000 molecular weight, methacrylicacid-methylmethacrylate 50:50 copolymer of 135,000 molecular weight,methacrylic acid-methylmethacrylate-30:70-copolymer of 135,000 mol. wt.,methacrylic acid-dimethylaminoethyl-methacrylate-ethylacrylate of750,000 mol. wt., methacrylic acid-methylmethacrylate-ethylacrylate of1,000,000 mol. wt., and ethylacrylate-methylmethacrylate-ethylacrylateof 550,000 mol. wt; and, (g) an enteric composition comprising a memberselected from the group consisting of cellulose acetyl phthalate,cellulose diacetyl phthalate, cellulose triacetyl phthalate, celluloseacetate phthalate, hydroxypropylmethylcellulose phathalate, sodiumcellulose acetate phthalate, cellulose ester phthalate, cellulose etherphthalate, methylcellulose phthalate, cellulose ester-ether phthalate,hydroxypropyl cellulose phthalate, alkali salts of cellulose acetatephthalate, alkaline earth salts of cellulose acetate phthalate, calciumsalt of cellulose acetate phthalate, ammonium salt of hydroxypropylmethylcellulose phthalate, cellulose acetate hexahydrophthalate,hydroxypropyl methylcellulose hexahydrophthalate, polyvinyl acetatephthalate diethyl phthalate, dibutyl phthalate, dialkyl phthalatewherein the alkyl comprises from 1 to 7 straight and branched alkylgroups, aryl phthalates, and other materials known to one or ordinaryskill in the art.

The semipermeable membrane of the osmotic device is formed of a materialthat is substantially permeable to the passage of fluid from theenvironment of use to the core and substantially impermeable to thepassage of active agent from the core. Many common materials that form asemipermeable wall which are known by those of ordinary skill in the artof pharmaceutical sciences are suitable for this purpose. Exemplarymaterials are cellulose esters, cellulose ethers and celluloseesters-ethers. However, it has been found that a semipermeable membranecomprising cellulose acetate (CA) and poly(ethylene glycol) (PEG), inparticular PEG 400, performs well when used in combination with theother materials required in the present osmotic device. This particularcombination of CA and PEG provides a semipermeable membrane that givesthe osmotic device a well controlled release profile for the activeagent in the core and that retains its chemical and physical integrityin the environment of use. The ratio of CA:PEG generally ranges fromabout 50-99% by weight of CA: about 50-1% by weight of PEG, and about95% by weight of CA: about 5% by weight of PEG. The ratio can be variedto alter permeability and ultimately the release profile of the osmoticdevice. Other suitable materials can include a selected member of thegroup of cellulose acylates such as cellulose acetate, cellulosediacetate, cellulose triacetate and combinations thereof. Many suitablepolymers, include those disclosed in Argentine Pat. No. 199,301, U.S.Pat. No. 6,004,582 and references cited herein, the disclosures of whichare hereby incorporated by reference.

Representative materials include a member selected from the groupconsisting of cellulose acylate, cellulose diacylate, cellulosetriacylate, cellulose acetate, cellulose diacetate, cellulosetriacetate, mono, di and tricellulose alkanylates, mono, di andtricellulose aroylates, and the like. Exemplary polymers includecellulose acetate having a D.S. up to 1 and an acetyl content up to 21%;cellulose acetate having an acetyl content of 32 to 39.8%; cellulosediacetate having a D.S. of 1 to 2 and an acetyl content of 21 to 35%;cellulose triacetate having a D.S. of 2 to 3 and an acetyl content of 35to 44.8%; and the like. More specific cellulosic polymers includecellulose propionate having a D.S. of 1.8 and a propionyl content of39.2 to 45% and a hydroxyl content of 2.8 to 5.4%; cellulose acetatebutyrate having a D.S. of 1.8, an acetyl content of 13 to 15% and abutyryl content of 34 to 39%; cellulose acetate butyrate having anacetyl content of 2 to 29%; a butyryl content of 17 to 53% and ahydroxyl content of 0.5 to 4.7%; cellulose triacylates having a D.S. of2.9 to 3 such as cellulose trivalerate, cellulose trilaurate, cellulosetripalmitate, cellulose trisuccinate, and cellulose trioclanoate;cellulose diacylates having a D.S. of 2.2 to 2.6 such as cellulosedisuccinate, cellulose dipalmitate, cellulose dioclanoate, cellulosedipentale, and the like. Additional semipermeable polymers includeacetaldehyde dimethyl acetate, cellulose acetate ethyl carbamate,cellulose acetate phthalate for use in environments having a low ph,cellulose acetate methyl carbamate, cellulose acetate dimethylaminoacetate, semipermeable polyamides, semipermeable polyurethanes,semipermeable sulfonated polystyrenes, cross-linked selectivelysemipermeable polymers formed by the coprecipitation of a polyanion anda polycation as disclosed in U.S. Pat. No. 3,173,876, No. 3,276,586, No.3,541,005, No. 3,541,006, and No. 3,546,142; semipermeable polymers asdisclosed by Loeb and Sourirajan in U.S. Pat. No. 3,133,132; lightlycross-linked polystyrene derivatives; cross-linked poly(sodium styrenesulfonate), cross-linked poly(vinylbenzyltrimethyl ammonium chloride),semipermeable polymers exhibiting a fluid permeability of 10.sup.-5 to10.sup.-1 (cc.mil/cm.sup.2.hr.atm) expressed as per atmosphere ofhydrostatic or osmotic pressure difference across the semipermeablewall. These and others polymers are disclosed in U.S. Pat. No.3,845,770, No. 3,916,899, No. 4,765,989 and No. 4,160,020; and inHandbook of Common Polymers (Scott, J. R. and Roff, W. J., eds.; 1971;CRC Press, Cleveland, Ohio).

The osmotic device of the invention comprises at least one passageway(pore, hole, or aperture) which communicates the exterior of thesemipermeable wall with the core of the device. The passageway can beformed according to any of the known methods of forming passageways in asemipermeable membrane. Such methods include, for example, 1) drilling ahole through the semipermeable membrane with a bit or laser; 2)including a water soluble material within the composition that forms thesemipermeable membrane such that a pore forms when the osmotic device isin an aqueous environment of use; 3) punching a hole through thesemipermeable membrane; or 4) employing a tablet punch having a pin topunch a hole through the semipermeable lamina. The passageway can passthrough the semipermeable wall and one or more of any other laminacoated onto the semipermeable membrane or between the semipermeablemembrane and the core. The passageway(s) can be shaped as desired. Insome embodiments, the passageway is laser drilled and is shaped as anoval, ellipse, slot, slit, cross or circle.

Methods of forming passageways in semipermeable membranes of osmoticdevices are disclosed in U.S. Pat. No. 4,088,864 to Theeuwes et al., No.4,016,880 to Theeuwes et al., No. 3,916,899 to Theeuwes et al., No.4,285,987 to Ayer et al., No. 4,783,337 to Wong et al., No. 5,558,879 toChen et al., No. 4,801,461 to Hamel et al., and No. 3,845,770 toTheeuwes et al., the disclosures of which are hereby incorporated byreference.

The core of the osmotic device tablet of the present invention willcomprise pseudoephedrine, at least one pharmaceutically acceptableexcipient and optionally one or more other materials. Generally, thetablet formulations will comprise about 0.1-99.9% by weight ofpseudoephedrine in the uncoated tablet core. Acceptable ranges may varyaccording to the desired therapeutic response, the tablet size, theamount and type of excipients used in the core of the device, the H1antagonist used and the intended use of the osmotic device.

When the controlled release tablet is an osmotic device, osmoticallyeffective solutes, osmotic agents or osmagents are added. Theseosmagents can aid in either the suspension or dissolution of the PS inthe core. Exemplary osmagents include organic and inorganic compoundssuch as salts, acids, bases, chelating agents, sodium chloride, lithiumchloride, magnesium chloride, magnesium sulfate, lithium sulfate,potassium chloride, sodium sulfite, calcium bicarbonate, sodium sulfate,calcium sulfate, calcium lactate, d-mannitol, urea, tartaric acid,raffinose, sucrose, alpha-d-lactose monohydrate, glucose, combinationsthereof and other similar or equivalent materials which are widely knownin the art. Osmagents can also be incorporated to the core of theosmotic device to control the release of Ps therefrom. U.S. Pat. No.4,077,407 to Theeuwes et al., the entire disclosure of which is herebyincorporated by reference, discloses suitable osmagents.

The tablets of the invention can also comprise adsorbents, antioxidants,buffering agents, colorants, flavorants, sweetening agents, tabletantiadherents, tablet binders, tablet and capsule diluents, tabletdirect compression excipients, tablet disintegrants, tablet glidants,tablet lubricants, tablet or capsule opaquants and/or tablet polishingagents.

As used herein, the term “adsorbent” is intended to mean an agentcapable of holding other molecules onto its surface by physical orchemical (chemisorption) means. Such compounds include, by way ofexample and without limitation, powdered and activated charcoal andother materials known to one of ordinary skill in the art.

As used herein, the term “antioxidant” is intended to mean an agentwhich inhibits oxidation and thus is used to prevent the deteriorationof preparations by the oxidative process. Such compounds include, by wayof example and without limitation, ascorbic acid, ascorbyl palmitate,butylated hydroxyanisole, butylated hydroxytoluene, hypophophorous acid,monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite,sodium formaldehyde sulfoxylate and sodium metabisulfite and othermaterials known to one of ordinary skill in the art.

As used herein, the term “buffering agent” is intended to mean acompound used to resist change in pH upon dilution or addition of acidor alkali. Such compounds include, by way of example and withoutlimitation, potassium metaphosphate, potassium phosphate, monobasicsodium acetate and sodium citrate anhydrous and dihydrate and othermaterials known to one of ordinary skill in the art.

As used herein, the term “sweetening agent” is intended to mean acompound used to impart sweetness to a preparation. Such compoundsinclude, by way of example and without limitation, aspartame, dextrose,glycerin, mannitol, saccharin sodium, sorbitol and sucrose and othermaterials known to one of ordinary skill in the art.

As used herein, the term “tablet antiadherents” is intended to meanagents which prevent the sticking of tablet formulation ingredients topunches and dies in a tableting machine during production. Suchcompounds include, by way of example and without limitation, magnesiumstearate, talc, calcium stearate, glyceryl behenate, PEG, hydrogenatedvegetable oil, mineral oil, stearic acid and other materials known toone of ordinary skill in the art.

As used herein, the term “tablet binders” is intended to mean substancesused to cause adhesion of powder particles in table granulations. Suchcompounds include, by way of example and without limitation, acacia,alginic acid, carboxymethylcellulose sodium, poly(vinylpyrrolidone),compressible sugar (e.g., NuTab), ethylcellulose, gelatin, liquidglucose, methylcellulose, povidone and pregelatinized starch and othermaterials known to one of ordinary skill in the art.

When needed, binders may also be included in the tablets. Exemplarybinders include acacia, tragacanth, gelatin, starch, cellulose materialssuch as methyl cellulose and sodium carboxy methyl cellulose, alginicacids and salts thereof, polyethylene glycol, guar gum, polysaccharide,bentonites, sugars, invert sugars, poloxamers (PLURONIC™ F68, PLURONIC™F127), collagen, albumin, gelatin, cellulosics in nonaqueous solvents,combinations thereof and the like. Other binders include, for example,polypropylene glycol, polyoxyethylene-polypropylene copolymer,polyethylene ester, polyethylene sorbitan ester, polyethylene oxide,combinations thereof and other materials known to one of ordinary skillin the art.

As used herein, the term “tablet and capsule diluent” or “fillers” isintended to mean inert substances used as fillers to create the desiredbulk, flow properties, and compression characteristics in thepreparation of tablets and capsules. Such compounds include, by way ofexample and without limitation, dibasic calcium phosphate, kaolin,lactose, sucrose, mannitol, microcrystalline cellulose, powderedcellulose, precipitated calcium carbonate, sorbitol, and starch andother materials known to one of ordinary skill in the art.

As used herein, the term “tablet direct compression excipient” isintended to mean a compound used in direct compression tabletformulations. Such compounds include, by way of example and withoutlimitation, dibasic calcium phosphate (e.g., Ditab) and other materialsknown to one of ordinary skill in the art.

As used herein, the term “tablet glidant” is intended to mean agentsused in tablet and capsule formulations to promote flowability of thegranulation. Such compounds include, by way of example and withoutlimitation, colloidal silica, cornstarch, talc, calcium silicate,magnesium silicate, colloidal silicon, silicon hydrogel and othermaterials known to one of ordinary skill in the art.

As used herein, the term “tablet lubricant” is intended to meansubstances used in tablet formulations to reduce friction during tabletcompression. Such compounds include, by way of example and withoutlimitation, calcium stearate, magnesium stearate, mineral oil, stearicacid, and zinc stearate and other materials known to one of ordinaryskill in the art.

As used herein, the term “tablet/capsule opaquant” is intended to mean acompound used to render a capsule or a tablet coating opaque. May beused alone or in combination with a colorant. Such compounds include, byway of example and without limitation, titanium dioxide, talc and othermaterials known to one of ordinary skill in the art.

As used herein, the term “tablet polishing agent” is intended to mean acompound used to impart an attractive sheen to coated tablets. Suchcompounds include, by way of example and without limitation, carnaubawax, white wax and other materials known to one of ordinary skill in theart.

As used herein, the term “tablet disintegrant” is intended to mean acompound used in solid dosage forms to promote the disruption of thesolid mass into smaller particles which are more readily dispersed ordissolved. Exemplary disintegrants include, by way of example andwithout limitation, starches such as corn starch, potato starch,pre-gelatinized and modified starches thereof, sweeteners, clays, suchas bentonite, microcrystalline cellulose(e.g., Avicel),carboxymethylcellulose calcium, cellulose polyacrilin potassium (e.g.,Amberlite), alginates, sodium starch glycolate, gums such as agar, guar,locust bean, karaya, pectin, tragacanth; crospovidone and othermaterials known to one of ordinary skill in the art.

As used herein, the term “colorant” is intended to mean a compound usedto impart color to solid (e.g., tablets) pharmaceutical preparations.Such compounds include, by way of example and without limitation, FD&CRed No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&CGreen No. 5, D&C Orange No. 5, D&C Red No. 8, caramel, and ferric oxide,red, other F.D. & C. dyes and natural coloring agents such as grape skinextract, beet red powder, beta-carotene, annato, carmine, turmeric,paprika, and other materials known to one of ordinary skill in the art.The amount of coloring agent used will vary as desired.

As used herein, the term “flavorant” is intended to mean a compound usedto impart a pleasant flavor and often odor to a pharmaceuticalpreparation. Exemplary flavoring agents or flavorants include syntheticflavor oils and flavoring aromatics and/or natural oils, extracts fromplants, leaves, flowers, fruits and so forth and combinations thereof.These may also include cinnamon oil, oil of wintergreen, peppermintoils, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leaveoil, oil of nutmeg, oil of sage, oil of bitter almonds and cassia oil.Other useful flavors include vanilla, citrus oil, including lemon,orange, grape, lime and grapefruit, and fruit essences, including apple,pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot andso forth. Flavors which have been found to be particularly usefulinclude commercially available orange, grape, cherry and bubble gumflavors and mixtures thereof. The amount of flavoring may depend on anumber of factors, including the organoleptic effect desired. Flavorswill be present in any amount as desired by those of ordinary skill inthe art. Particularly flavors are the grape and cherry flavors andcitrus flavors such as orange.

The present tablets can also employ one or more commonly known surfaceactive agents or cosolvents that improve wetting or disintegration ofthe tablet core or layers.

Plasticizers can also be included in the tablets to modify theproperties and characteristics of the polymers used in the coats or coreof the tablets. As used herein, the term “plasticizer” includes allcompounds capable of plasticizing or softening a polymer or binder usedin invention. The plasticizer should be able to lower the meltingtemperature or glass transition temperature (softening pointtemperature) of the polymer or binder. Plasticizers, such as lowmolecular weight PEG, generally broaden the average molecular weight ofa polymer in which they are included thereby lowering its glasstransition temperature or softening point. Plasticizers also generallyreduce the viscosity of a polymer. It is possible the plasticizer willimpart some particularly advantageous physical properties to the osmoticdevice of the invention.

Plasticizers useful in the invention can include, by way of example andwithout limitation, low molecular weight polymers, oligomers,copolymers, oils, small organic molecules, low molecular weight polyolshaving aliphatic hydroxyls, ester-type plasticizers, glycol ethers,poly(propylene glycol), multi-block polymers, single block polymers, lowmolecular weight poly(ethylene glycol), citrate ester-type plasticizers,triacetin, propylene glycol and glycerin. Such plasticizers can alsoinclude ethylene glycol, 1,2-butylene glycol, 2,3-butylene glycol,styrene glycol, diethylene glycol, triethylene glycol, tetraethyleneglycol and other poly(ethylene glycol) compounds, monopropylene glycolmonoisopropyl ether, propylene glycol monoethyl ether, ethylene glycolmonoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate,ethyl lactate, butyl lactate, ethyl glycolate, dibutylsebacate,acetyltributylcitrate, triethyl citrate, acetyl triethyl citrate,tributyl citrate and allyl glycolate. All such plasticizers arecommercially available from sources such as Aldrich or Sigma ChemicalCo. It is also contemplated and within the scope of the invention, thata combination of plasticizers may be used in the present formulation.The PEG based plasticizers are available commercially or can be made bya variety of methods, such as disclosed in Poly(ethylene glycol)Chemistry: Biotechnical and Biomedical Applications (J. M. Harris, Ed.;Plenum Press, NY) the disclosure of which is hereby incorporated byreference.

The tablets of the invention can also include oils, for example, fixedoils, such as peanut oil, sesame oil, cottonseed oil, corn oil and oliveoil; fatty acids, such as oleic acid, stearic acid and isotearic acid;and fatty acid esters, such as ethyl oleate, isopropyl myristate, fattyacid glycerides and acetylated fatty acid glycerides. It can also bemixed with alcohols, such as ethanol, isopropanol, hexadecyl alcohol,glycerol and propylene glycol; with glycerol ketals, such as2,2-dimethyl-1,3-dioxolane-4-methanol; with ethers, such aspoly(ethyleneglycol) 450, with petroleum hydrocarbons, such as mineraloil and petrolatum; with water, or with mixtures thereof; with orwithout the addition of a pharmaceutically suitable surfactant,suspending agent or emulsifying agent.

Soaps and synthetic detergents may be employed as surfactants and asvehicles for detergent compositions. Suitable soaps include fatty acidalkali metal, ammonium, and triethanolamine salts. Suitable detergentsinclude cationic detergents, for example, dimethyl dialkyl ammoniumhalides, alkyl pyridinium halides, and alkylamine acetates; anionicdetergents, for example, alkyl, aryl and olefin sulfonates, alkyl,olefin, ether and monoglyceride sulfates, and sulfosuccinates; nonionicdetergents, for example, fatty amine oxides, fatty acid alkanolamides,and poly(oxyethylene)-block-poly(oxypropylene) copolymers; andamphoteric detergents, for example, alkyl β-aminopropionates and2-alkylimidazoline quaternary ammonium salts; and mixtures thereof.

Various other components, not otherwise listed above, can be added tothe present formulation for optimization of a desired active agentrelease profile including, by way of example and without limitation,glycerylmonostearate, nylon, cellulose acetate butyrate, d,1-poly(lactic acid), 1,6-hexanediamine, diethylenetriamine, starches,derivatized starches, acetylated monoglycerides, gelatin coacervates,poly (styrene—maleic acid) copolymer, glycowax, castor wax, stearylalcohol, glycerol palnitostearate, poly(ethylene), poly(vinyl acetate),poly(vinyl chloride), 1,3-butylene-glycoldimethacrylate,ethyleneglycol-dimethacrylate and methacrylate hydrogels.

It should be understood, that compounds used in the art ofpharmaceutical formulation generally serve a variety of functions orpurposes. Thus, if a compound named herein is mentioned only once or isused to define more than one term herein, its purpose or function shouldnot be construed as being limited solely to that named purpose(s) orfunction(s).

By the term “effective amount”, it is understood that, with respect to,for example, pharmaceuticals, a therapeutically effective amount iscontemplated. A therapeutically effective amount is the amount orquantity of pseudoephedrine, or H1 antagonist, which is sufficient toelicit the required or desired therapeutic response, or in other words,the amount which is sufficient to elicit an appreciable biologicalresponse when administered to a patient.

The tablets of the invention can assume any shape or form known in theart of pharmaceutical sciences. The device of the invention can be apill, sphere, tablet, bar, plate, paraboloid of revolution, ellipsoid ofrevolution or the like. The tablets can also include surface markings,cuttings, grooves, letters and/or numerals for the purposes ofdecoration, identification and/or other purposes.

The tablets of the invention can be prepared according to the methodsdisclosed herein or those well known in the art, more specificallyaccording to the methods disclosed in the disclosure incorporated hereinby reference. For example, according to one manufacturing technique,pseudoephedrine and excipients that comprise the core are mixed insolid, semisolid or gelatinous form, then moistened and sieved through aspecified screen to obtain granules. The granules are then dried in adryer and compressed, for example, by punching to form uncoated cores.The compressed and uncoated cores are then covered with a semipermeablemembrane. Subsequently, the semipermeable membrane surrounding the coreshould be perforated with, for example, laser equipment. Finally, anexternal coat containing the H1 antagonist is applied to thesemipermeable membrane.

The external coat can be applied as a compression coating, but it isgenerally applied as a sprayed coating. The sprayed coating is thinnerand lighter than the compression coating, and an osmotic deviceincluding the sprayed on external coating is, therefore, smaller than asimilar osmotic device having a compression coat. Moreover, the use of asprayed-on drug-containing water soluble coating permits the loading ofhigher amounts of drug than the use of a compression-coateddrug-containing water soluble coating. A smaller size osmotic devicegenerally results in increased patient compliance in taking the osmoticdevice and is therefore advantageous.

The tablets of the invention can be coated with a finish coat as iscommonly done in the art to provide the desired shine, color, taste orother aesthetic characteristics. Materials suitable for preparing thefinish coat are well known in the art and found in the disclosures ofmany of the references cited and incorporated by reference herein.

The advantages of the present system over known systems foradministering pseudoephedrine in combination with an H1 antagonist isimproved therapeutic benefit, simplified manufacturing, and increasedpatient compliance.

The following examples should not be considered exhaustive, but merelyillustrative of only a few of the many embodiments contemplated by thepresent invention. The methods described herein can be followed toprepare osmotic devices according to the invention.

EXAMPLE 1

The following general method was used to prepare osmotic devicesaccording to the invention. In one embodiment, a large scale batch ofpseudoephedrine HCl (240 mg) and loratadine (10 mg) osmotic devicetablets was prepared by mixing 240.00 g of pseudoephedrine HCl, 81.00 gof osmagent, 36.00 g of diluent and 50.00 g of binder. The mixture waswetted with a blend of 90.00 ml of alcohol 96° and 3.00 g ofplasticizer. The blend was granulated and dried at 40-50° C. for 3hours; then, it was screened and mixed with 2.50 g of glidant. The blendwas mixed to homogeneity and 7.50 g of lubricant was added. The finalblend was tabletted using biconcaves, 9.25-mm diameter punches to formuncoated cores. Core weight: 420.0 mg; hardness from 8 to 12 kp.

A first composition to cover the cores was prepared as follows: 40.85 gof Cellulose ester and 2.15 g of plasticizer was added to 495.0 ml of ablend of organic solvents. This polymer mixture was sprayed onto thetablets in a conventional pan coater to obtain film-coated tablets whosemembrane coating weighed approximately 43.0 mg. A 0.50-mm hole was laserdrilled through the coating in one face of the tablet.

The second coating was prepared by mixing 3.90 g of water solublepolymer, 3.50 g of opaquant, 12.58 g of Talc and 18.00 mg of colorant inIsopropyl Alcohol. This polymer mixture was sprayed onto the tablets ina conventional pan coater to obtain film-coated tablets whose membranecoating weighed approximately 20 mg.

The third coating was prepared by mixing 10.00 g of Loratadine, 30.00 gof film forming polymer, 5.40 g of plasticizer, 9.60 g of water solublepolymer (disintegrant) and 0.60 g of glidant in Purified Water. Thispolymer mixture was sprayed onto the tablets in a conventional pancoater to obtain film-coated tablets whose membrane coating weighed 55.6mg approximately.

The final coating was prepared by mixing 23.46 g of film formingpolymer, 1.56 g of plasticizer, 4.95 g of opaquant and 7.53 g of talc ina blend of organic solvents. This composition was sprayed onto thedrug-containing coating in a conventional pan coater.

The osmagent, diluent, binder, plasticizer, glidant, disintegrant,lubricant, cellulose ester, water soluble polymer, opaquant, and filmforming polymer used in the present formulation were selected from therespective groups of ingredients set forth above. The organic solventsused herein can include, for example, ethanol, methanol, isopropanol,methylene chloride, and others typically used in the pharmaceuticalsciences.

The above method was used to prepare tablets having the followingformulation:

CORE (420 mg) Pseudoephedrine Hydrochloride 240.000 mg Osmagent 80-85 mgDiluent 30-40 mg Binder 45-55 mg Plasticizer 0.5-5 mg Glidant 0.5-5 mgLubricant 0.5-10 mg COATING A (43 mg) (semipermeable membrane) CelluloseEster 35-45 mg Plasticizer 0.5-5 mg COATING B (20 mg) (inert watersoluble lamina) Water soluble polymer 1-5 mg Opaquant 1-5 mg Talc 5-15mg Colorant 0.01-0.5 mg COATING C (55.6 mg) (drug-containing solublelamina) Loratadine 10.000 mg Film forming polymer 20-40 mg Plasticizer1-10 mg Disintegrant or water soluble polymer 5-15 mg Glidant 0.1-5 mgCOATING D (polish coating) Film forming polymer 10-20 mg Plasticizer0.1-5 mg Opaquant 1-5 mg Talc 1-10 mg

EXAMPLE 2

The following general method was used to prepare other osmotic devicesaccording to the invention. In one embodiment, D-pseudoephedrinehydrochloride (2,400 g), osmagent (810 g), diluent (360.0 g) and binder(500 g) are mixed in a laboratory mixer. The mixture is then sievedthrough a 40 mesh screen and kneaded while adding of solution containingplasticizer (10.7%) in ethyl alcohol. The wet product is sieved throughan 8 mesh screen and dried in a heated oven for 12 hours at 45° C. Amixture of glidant (25.0 g) and lubricant (75.0 g), previously sievedthrough a 50 mesh screen, is added to the dry granulate. The resultinggranulate mixture is compressed in a compressor with 10 mm diameterpunches to form uncoated cores.

Resulting uncoated cores are then coated with a solution containingcellulose ester (95%) and plasticizer (5%) in a blend of organicsolvents to form semipermeable membrane coated cores.

The semipermeable membrane coat of each core is then perforated withlaser equipment to form at least one passageway through thesemipermeable coat.

The perforated cores are then covered with a suspension comprising watersoluble polymer (disintegrant) (19.56%), opaquant (16.59%), glidant(62.2%), and colorant (1.66%) in organic solvent to form cores coatedwith an inert and erodible water soluble polymer coat.

The coated cores having sealed passageways are subjected to a coatingprocess through compression with a granulate as follows. In a laboratorymixer-kneader, loratadine (80 g), first filler (1516.0 g), diluent (1600g), second filler (400 g) are mixed. This wet mixture is sieved througha 40 mesh screen and later kneaded with a solution containing binder(41.18%), first plasticizer (47.06%), and second plasticizer (11.16%) indeionized water. The wet mixture is then sieved through a 10 mesh screenand dried in a heated oven at 45° C. for 12 hours. The dried granulateis sieved through a 20 mesh screen and then mixed with a previouslyprepared mixture of glidant (16.0 g) and lubricant (48.0 g) and thefinal mixture is sieved through a 50 mesh screen to form a granulate.This resulting granulate is applied over the coated core throughcompression, as previously described. These particular devices have a 14mm outer diameter and containing a 10 mm outer diameter osmotic core.

Finally, a finish coat is applied to the devices by applying asuspension comprising film forming polymer (60.27%), plasticizer(17.18%), and opaquant (22.55%) in a blend of organic solventsoptionally containing water.

The osmagent, diluent, binder, plasticizer, glidant, lubricant,cellulose ester, water soluble polymer (disintegrant), opaquant, andfilm forming polymer used in the present formulation were selected fromthe respective groups of ingredients set forth above. The organicsolvents used herein can include, for example, ethanol, methanol,isopropanol, methylene chloride, and others typically used in thepharmaceutical sciences.

EXAMPLE 3

D-pseudoephedrine (2,400.0 g), osmagent (810.02 g), diluent (1335.0 g)and water soluble polymer (400.0 g) are mixed in a laboratory mixer. Themixture is then sieved through a 40 mesh screen and kneaded while addinga solution containing water soluble polymer (30%) in ethyl alcohol (96%in water). The wet product is sieved through a 10 mesh screen and driedin a heated oven for 5 hours at 45° C. A mixture of glidant (29.97 g)and lubricant (75.0 g), previously sieved through a 50 mesh screen, isadded to a dry granulate. The resulting granulate mixture is compressedin a compressor with 10 mm diameter punches to form uncoated cores.

Resulting uncoated cores are then coated with a solution containingcellulose ester (95%) and plasticizer (5%) in a mixture of organicsolvents to form semipermeable membrane coated cores.

The semipermeable membrane coat of each core is then perforated withlaser equipment to form at least one passageway through thesemipermeable coat.

The perforated cores are then covered with a suspension comprising watersoluble copolymer (disintegrant) (19.56%), opaquant (16.59), filler(62.2%), and colorant (1.66%) in organic solvent (25%) to form corescoated having passageways sealed with the polymer coat of the invention.

The coated cores having blocked passageways are then coated with asuspension comprising astemizol (52.00%); suspending agent (2.65%);disintegrant (15.63%); first plasticizer (1.63%); water soluble polymer(25.95%); polysorbate 20 (1.06%), and second plasticizer (1.06%) inorganic solvent (4%).

A finish coat is then applied by spraying the following suspension ontothe cores: film forming polymer (60.27%); plasticizer (17.18%); opaquant(21.50%); colorant (1.05%), in a mixture of organic solvents 50% firstsolvent/50% second solvent; followed by drying of the finish coat.

The osmagent, diluent, binder, plasticizer, glidant, lubricant,cellulose ester, water soluble polymer (disintegrant), opaquant, andfilm forming polymer used in the present formulation were selected fromthe respective groups of ingredients set forth above. The organicsolvents used herein can include, for example, ethanol, methanol,isopropanol, methylene chloride, and others typically used in thepharmaceutical sciences.

EXAMPLE 4

The procedure of Example 1 was used to prepare the following osmoticdevices, except that the tablets contained the following ingredients inthe amounts indicated.

CORE Pseudoephedrine Hydrochloride 240.00 mg Osmagent 70-90 mg Diluent30-40 mg Binder 40-60 mg Plasticizer 0.5-5 mg Glidant 0.5-5 mg Lubricant5-10 mg COATING A Cellulose ester 35-45 mg Plasticizer 0.5-5 mg COATINGB Water soluble polymer 1-5 mg Opaquant 0.5-5 mg Filler 5-15 mg Colorant0.01-0.05 mg COATING C Fexofenadine Hydrochloride 180.00 mg Film formingpolymer 20-25 mg Disintegrant 50-70 mg Plasticizer 5-15 mg Filler 0.5-10mg COATING D Film forming polymer 1-7.5 mg Plasticizer 0.5-5 mg Opaquant1-10 mg Filler 0.1-5 mg Water soluble polymer 1-5 mg

The osmagent, diluent, binder, plasticizer, glidant, lubricant,cellulose ester, water soluble polymer, disintegrant, opaquant, and filmforming polymer used in the present formulation were selected from therespective groups of ingredients set forth above. The organic solventsused herein can include, for example, ethanol, methanol, isopropanol,methylene chloride, and others typically used in the pharmaceuticalsciences.

EXAMPLE 5

The procedure of Example 1 was used to prepare the following osmoticdevices, except that the tablets contained the following ingredients inthe amounts indicated.

CORE Pseudoephedrine Hydrochloride 240.00 mg Osmagent 70-90 mg Diluent30-40 mg Binder 40-60 mg Plasticizer 0.5-5 mg Glidant 0.5-5 mg Lubricant5-10 mg COATING A Cellulose Ester 40-50 mg Plasticizer 1-3 mg COATING BWater soluble polymer 1-5 mg Opaquant 0.5-5 mg Filler 5-15 mg Colorant0.01-0.05 mg COATING C Fexofenadine Hydrochloride 120.00 mg Film formingpolymer 10-20 mg Water soluble copolymer 20-30 mg Plasticizer 2.5-7.5 mgDisintegrant 5-10 mg COATING D Film forming polymer 10-15 mg Plasticizer2-5 mg Opaquant 5-10 mg Filler 0.5-5 mg Disintegrant 1-5 mg

The osmagent, diluent, binder, plasticizer, glidant, lubricant,disintegrant, filler, cellulose ester, water soluble polymer, watersoluble copolymer, opaquant, and film forming polymer used in thepresent formulation were selected from the respective groups ofingredients set forth above. The organic solvents used herein caninclude, for example, ethanol, methanol, isopropanol, methylenechloride, and others typically used in the pharmaceutical sciences.

A tablet made according to this procedure provides a PS release profilesimilar to the ones depicted in FIGS. 1 and 2 and an FEX release profilesimilar to the one depicted in FIG. 3.

EXAMPLE 6

The procedure of Example 1 was used to prepare the following osmoticdevices, except that the tablets contained the following ingredients inthe amounts indicated. More over, the core, Coating A and Coating B weremade as described in Example 5.

COATING C Epinastine Hydrochloride 20.00 mg Film forming polymer 20-30mg Dispersant 0.1-2 mg Plasticizer 2-8 mg Disintegrant 5-10 mg COATING DWater soluble polymer 10-15 mg Plasticizer 0.1-1 mg Opaquant 0.1-5 mgFiller 1-5 mg Disintegrant 1-5 mg

The osmagent, diluent, binder, plasticizer, glidant, lubricant,disintegrant, filler, cellulose ester, water soluble polymer, watersoluble copolymer, opaquant, and film forming polymer used in thepresent formulation were selected from the respective groups ofingredients set forth above. The organic solvents used herein caninclude, for example, ethanol, methanol, isopropanol, methylenechloride, and others typically used in the pharmaceutical sciences.

A tablet made according to this procedure provides a PS release profilesimilar to the ones depicted in FIGS. 1 and 2 and an epinastine releaseprofile similar to the one depicted in FIG. 3.

EXAMPLE 7

The procedure of Example 1 was used to prepare the following osmoticdevices, except that the tablets contained the following ingredients inthe amounts indicated. In addition, the core, Coating A and Coating Bwere made according to Example 5.

COATING C Fexofenadine Hydrochloride 120.00 mg Film forming polymer20-40 mg Plasticizer 1-7.5 mg Disintegrant 20-30 mg COATING D Filmforming polymer 5-10 mg Plasticizer 1-5 mg Opaquant 5-10 mg Filler 0.1-5mg Disintegrant 1-5 mg

The osmagent, diluent, binder, plasticizer, glidant, lubricant,disintegrant, filler, cellulose ester, water soluble polymer, watersoluble copolymer, opaquant, and film forming polymer used in thepresent formulation were selected from the respective groups ofingredients set forth above. The organic solvents used herein caninclude, for example, ethanol, methanol, isopropanol, methylenechloride, and others typically used in the pharmaceutical sciences.

A tablet made according to this procedure provides a PS release profilesimilar to the ones depicted in FIGS. 1 and 2 and an FEX release profilesimilar to the one depicted in FIG. 3.

The devices of the invention can contain 60-240 mg, 120-240 mg or180-240 mg of pseudoephedrine as either its free-base, salt form orcombination thereof.

The above is a detailed description of particular embodiments of theinvention. It is recognized that departures from the disclosedembodiments may be made within the scope of the invention and thatobvious modifications will occur to a person skilled in the art. Thoseof skill in the art should, in light of the present disclosure,appreciate that many changes can be made in the specific embodimentswhich are disclosed herein and still obtain a like or similar resultwithout departing from the spirit and scope of the invention. All of theembodiments disclosed and claimed herein can be made and executedwithout undue experimentation in light of the present disclosure.

I claim:
 1. An osmotic device comprising: (a) a core comprising atherapeutically effective amount of pseudoephedrine which is deliveredat a controlled rate over a period of about 18-24 hours; (b) asemipermeable membrane surrounding the core and a passageway through thesemipermeable membrane; (c) an inert water soluble or erodible coatingsurrounding the semipermeable membrane and plugging the passageway; and(d) a fexofenadine-containing water soluble or erodible coatingsurrounding the inert water soluble coating for delivering all of thefexofenadine at a rapid rate over a period of less than about 90 min,wherein: 1) 10-25% of the PS is released within 3 hours; 2) 25-50% ofthe PS is released within 7 hours; 3) 50-66% of the PS is releasedwithin 11 hours; 4) 66-79% of the PS is released within 15 hours; and 5)79-100% of the PS is released within 23 hours after exposure to anaqueous environment.
 2. The osmotic device of claim 1, wherein about60-240 mg of pseudoephedrine are present and about 60-180 mg offexofenadine are present.
 3. The osmotic device of claim 1, wherein thedrug-containing water soluble or erodible coating is present in anamount of at least about 25% wt. based upon the total weight of theosmotic device.
 4. The osmotic device of claim 1, wherein thedrug-containing water soluble or erodible coating is present in anamount of about 25-40% wt. based upon the total weight of the osmoticdevice.
 5. The osmotic device of claim 1, wherein the drug-containingwater soluble or erodible coating is present in an amount of about30-40% wt. based upon the total weight of the osmotic device.
 6. Theosmotic device of claim 1, wherein the pseudoephedrine is released at azero-order or pseudo-zero order rate.
 7. The osmotic device of claim 1,wherein all of the fexofenadine is released over a period of less thanabout 60 min.
 8. The osmotic device of claim 1, wherein all of thefexofenadine is released over a period of less than about 45 min.
 9. Theosmotic device of claim 1, wherein all of the fexofenadine is releasedover a period of less than about 30 min.
 10. The osmotic device of claim1, wherein all of the fexofenadine is released over a period of lessthan about 20 min.
 11. The osmotic device of claim 1, wherein all of thefexofenadine is released over a period of less than about 10 min. 12.The osmotic device of claim 2, wherein: the core further comprises anosmagent, a diluent and a binder; the semipermeable membrane comprises acellulose ester and a plasticizer; the inert water soluble or erodiblecoating comprises a water soluble polymer, an opaquant and a filler; andthe fexofenadine-containing water soluble or erodible coating furthercomprises a film forming polymer and a disintegrant.
 13. The osmoticdevice of claim 12, wherein: the osmagent is selected from the groupconsisting of sodium chloride, salt, mannitol, acid, sugar, base,calcium salt, sodium salt, and lactose; the diluent is selected from thegroup consisting of microcrystalline cellulose, lactose, sucrose,mannitol, cellulose, starch, sorbitol, dibasic calcium phosphate, andcalcium carbonate; the binder is selected from the group consisting ofpoly(vinylpyrrolidone), povidone, sodium carboxymethylcellulose, alginicacid, poly(ethylene glycol), guar gum, polysaccharide, bentonite clay,sugar, poloxamer, collagen, albumin, gelatin, poly(propylene glycol),and poly(ethylene oxide); the cellulose ester is selected from the groupconsisting of cellulose acetate, cellulose acylate, cellulose fatty acidester, and cellulose acetate phthalate; the plasticizer is independentlyselected at each occurrence from the group consisting of poly(ethyleneglycol), low molecular weight polymer, citrate ester, triacetin,propylene glycol, glycerin, sorbitol lactate, ethyl lactate, butyllactate, ethyl glycolate, and dibutylsebacate; the water soluble polymeris independently selected at each occurrence from the group consistingof hydroxypropyl methylcellulose, poly(vinlypyrrolidone)-(vinyl acetate)copolymer, poly(vinylpyrrolidone), methyl methacrylate, calciumpectinate, poly(ethylene-vinyl acetate), hydroxylalkyl alkylcellulose,polyvinylalcohol, polyethylene oxide, a blend of gelatin andpolyvinyl-pyrrolidone, gelatin, glucose, saccharide, povidone,copovidone, and polysaccharide gum; the film forming polymer is selectedfrom the group consisting of hydroxypropyl methylcellulose, andpoly(vinylpyrrolidone); the disintegrant is selected from the groupconsisting of crospovidone, bentonite clay, microcrystalline cellulose,starch, carboxymethylcellulose, alginate, sodium starch glycolate, andgum.
 14. The osmotic device of claim 13, wherein: the opaquant isselected from the group consisting of titanium dioxide and talc; and thefiller is selected from the group consisting of talc and starch.
 15. Theosmotic device of claim 12, wherein: the osmagent is present in anamount ranging from 70-90 mg; the diluent is present in an amountranging from 30-40 mg; the binder is present in an amount ranging from40-60 mg; the cellulose ester is present in an amount ranging from 35-45mg; the film-forming polymer in the fexofenadine-containing watersoluble or erodible coating is present in an amount ranging from 20-25mg; and the disintegrant in the fexofenadine-containing water soluble orerodible coating is present in an amount ranging from 50-70 mg.
 16. Theosmotic device of claim 12, wherein: the osmagent is present in anamount ranging from 70-90 mg; the diluent is present in an amountranging from 30-40 mg; the binder is present in an amount ranging from40-60 mg; the cellulose ester is present in an amount ranging from 40-50mg; the film-forming polymer in the fexofenadine-containing watersoluble or erodible coating is present in an amount ranging from 10-20mg; the disintegrant in the fexofenadine-containing water soluble orerodible coating is present in an amount ranging from 5-10 mg; and thefexofenadine-containing water soluble or erodible coating furthercomprises a water soluble copolymer present in an amount ranging from20-30 mg.
 17. The osmotic device of claim 12, wherein: the osmagent ispresent in an amount ranging from 70-90 mg; the diluent is present in anamount ranging from 30-40 mg; the binder is present in an amount rangingfrom 40-60 mg; the cellulose ester is present in an amount ranging from35-45 mg; the film-forming polymer in the fexofenadine-containing watersoluble or erodible coating is present in an amount ranging from 20-40mg; and the disintegrant in the fexofenadine-containing water soluble orerodible coating is present in an amount ranging from 20-30 mg.
 18. Amethod of treating a respiratory congestion related disorder in a mammalcomprising the step of administering an osmotic device according to anyone of claims 1-3, 6-7, 12-13, 15-17.
 19. An osmotic device comprising:(a) a core comprising a therapeutically effective amount ofpseudoephedrine which is delivered at a controlled rate over a period ofabout 18-24 hours; (b) a semipermeable membrane surrounding the core anda passageway through the semipermeable membrane; (c) an inert watersoluble or erodible coating surrounding the semipermeable membrane andplugging the passageway; and (d) a fexofenadine-containing water solubleor erodible coating surrounding the inert water soluble coating fordelivering all of the fexofenadine at a rapid rate over a period of lessthan about 90 min, wherein: 1) 9-11% of the PS is released within 3hours; 2) 19-22% of the PS is released within 5 hours; 3) 28-31% of thePS is released within 7 hours; 4) 35-40% of the PS is released within 9hours; 5) 45-50% of the PS is released within 11 hours; 6) 50-55% of thePS is released within 13 hours; 7) 60-65% of the PS is released within15 hours; and 8) at least 75% of the PS is released within 23 hoursafter exposure to an aqueous environment.
 20. The osmotic device ofclaim 19, wherein about 60-240 mg of pseudoephedrine are present andabout 60-180 mg of fexofenadine are present.
 21. The osmotic device ofclaim 19, wherein the drug-containing water soluble or erodible coatingis present in an amount of at least about 25% wt. based upon the device.22. The osmotic device of claim 19, wherein the drug-containing watersoluble or erodible coating is present in an amount of about 25-40% wt.based upon the total weight of the osmotic device.
 23. The osmoticdevice of claim 19, wherein the drug-containing water soluble orerodible coating is present in an amount of about 30-40% wt. based uponthe total weight of the osmotic device.
 24. The osmotic device of claim19, wherein the pseudoephedrine is released at a zero-order orpseudo-zero order rate.
 25. The osmotic device of claim 19, wherein allof the fexofenadine is released over a period of less than about 60 min.26. The osmotic device of claim 19, wherein all of the fexofenadine isreleased over period of less than about 45 min.
 27. The osmotic deviceof claim 19, wherein all of the fexofenadine is released ever a periodof less than about 30 min.
 28. The osmotic device of claim 19, whereinall of the fexofenadine is released over a period of less than about 20min.
 29. The osmotic device of claim 19, wherein all of the fexofenadineis released over a period of less than about 10 min.
 30. The osmoticdevice of claim 20, wherein: the core further comprises an osmagent, adiluent and a binder; the semipermeable membrane comprises a celluloseester and a plasticizer; the inert water soluble or erodible coatingcomprises a water soluble polymer, an opaquant and a filler; and thefexofenadine-containing water soluble or erodible coating furthercomprises a film forming polymer and a disintegrant.
 31. The osmoticdevice of claim 30, wherein: the osmagent is selected from the groupconsisting of sodium chloride, salt, mannitol, acid, sugar, base,calcium salt, sodium salt, and lactose; the diluent is selected from thegroup consisting of microcrystalline cellulose, lactose, sucrose,mannitol, cellulose, starch, sorbitol, dibasic calcium phosphate, andcalcium carbonate; the binder is selected from the group consisting ofpoly(vinylpyrrolidone), povidone, sodium carboxymethylcellulose, alginicacid, poly(ethylene glycol), guar gum, polysaccharide, bentonite clay,sugar, poloxamer, collagen, albumin, gelatin, poly(propylene glycol),and poly(ethylene oxide); the cellulose ester is selected from the groupconsisting of cellulose acetate, cellulose acylate, cellulose fatty acidester, and cellulose acetate phthalate; the plasticizer is independentlyselected at each occurrence from the group consisting of poly(ethyleneglycol), low molecular weight polymer, citrate ester, triacetin,propylene glycol, glycerin, sorbitol lactate, ethyl lactate, butyllactate, ethyl glycolate, and dibutylsebacate; the water soluble polymeris independently selected at each occurrence from the group consistingof hydroxypropyl methylcellulose, poly(vinlypyrrolidone)-(vinyl acetate)copolymer, poly(vinylpyrrolidone), methyl methacrylate, calciumpectinate, poly(ethylene-vinyl acetate), hydroxylalkyl alkylcellulose,polyvinylalcohol, polyethylene oxide, a blend of gelatin andpolyvinyl-pyrrolidone, gelatin, glucose, saccharide, povidone,copovidone, and polysaccharide gum; the film forming polymer is selectedfrom the group consisting of hydroxypropyl methylcellulose, andpoly(vinylpyrrolidone); the disintegrant is selected from the groupconsisting of crospovidone, bentonite clay, microcrystalline cellulose,starch, carboxymethyleellulose, alginate, sodium starch glycolate, andgum.
 32. The osmotic device of claim 31 wherein: the opaquant isselected from the group consisting of titanium dioxide and talc; and thefiller is selected from the group consisting of talc and starch.
 33. Theosmotic device of claim 30, wherein: the osmagent is present in anamount ranging from 70-90 mg; the diluent is present in an amountranging from 30-40 mg; the binder is present in an amount ranging from40-60 mg; the cellulose ester is present in an amount ranging from 35-45mg; the film-forming polymer in the fexofenadine-containing watersoluble or erodible coating is present in an amount ranging from 20-25mg; and the disintegrant in the fexofenadine-containing water soluble orerodible coating is present in an amount ranging from 50-70 mg.
 34. Theosmotic device of claim 30, wherein: the osmagent is present in anamount ranging from 70-90 mg; the diluent is present in an amountranging from 30-40 mg; the binder is present in an amount ranging from40-60 mg; the cellulose ester is present in an amount ranging from 40-50mg; the film-forming polymer in the fexofenadine-containing watersoluble or erodible coating is present in an amount ranging from 10-20mg; the disintegrant in the fexofenadine-containing water soluble orerodible coating is present in an amount ranging from 5-10 mg; and thefexofenadine-containing water soluble or erodible coating furthercomprises a water soluble copolymer present in an amount ranging from20-30 mg.
 35. The osmotic device of claim 30, wherein: the osmagent ispresent in an amount ranging from 70-90 mg; the diluent is present in anamount ranging from 30-40 mg; the binder is present in an amount rangingfrom 40-60 mg; the cellulose ester is present in an amount ranging from35-45 mg; the film-forming polymer in the fexofenadine-containing watersoluble or erodible coating is present in an amount ranging from 20-40mg; and the disintegrant in the fexofenadine-containing water soluble orerodible coating is present in an amount ranging from 20-30 mg.
 36. Anosmotic device comprising: (a) a core comprising a therapeuticallyeffective amount of pseudoephedrine which is delivered at a controlledrate over a period of about 18-24 hours; (b) a semipermeable membranesurrounding the core and a passageway through the semipermeablemembrane; (c) an inert water soluble or erodible coating surrounding thesemipermeable membrane and plugging the passageway; and (d) afexofenadine-containing water soluble or erodible coating surroundingthe inert water soluble coating for delivering all of the fexofenadineat a rapid rate over a period of less than about 90 min, wherein: 1)5-23% of the PS is released within 3 hours; 2) 20-52% of the PS isreleased within 7 hours; 3) 36-72% of the PS is released within 11hours; 4)53-82% of the PS is released within 15 hours; and 5) at least75% of the PS is released within 23 hours after exposure to an aqueousenvironment.
 37. A method of treating a respiratory congestion relateddisorder in a mammal rising the step of administering an osmotic deviceaccording to any one of claims 19-35 or 36.